Role of neuropilin‐2 in the ipsilateral growth of midbrain dopaminergic axons

Axonal projections in the CNS can be categorized as either crossed or uncrossed. Crossing and uncrossing of axons has been explained by attractive and repulsive molecules like N etrin‐1 and S lits, which are secreted by midline structures. However, uncrossed projections can be established even in double knockout mice of slit1 and slit2 or of roundabout1 ( robo1 ) and robo2 , two receptors for S lits. Here, we found that a novel mechanism mediated by N europilin‐2 ( N rp2) contributes to the formation of uncrossed projections of midbrain dopaminergic neurons (m DAN s). N rp2 transcriptional activities were detected in a subset of m DAN s, and its protein was expressed in m DAN axons growing through the ipsilateral diencephalon. In nrp2 lacZ/lacZ mice, mDAN axons aberrantly grew toward the ventral midline and even crossed it, suggesting that Nrp2 is necessary for the development of m DAN ipsilateral projections. We investigated the involvement of S emaphorin 3 B ( S ema3 B ) and S ema3 F , two ligands of N rp2, by analysing m DAN axon trajectories in single or double knockout mice. In both cases, m DAN axons still projected ipsilaterally, suggesting the involvement mechanisms independent of these S ema3s. N rp2‐deficient m DAN axons retained their responsiveness to S lit2, demonstrating that aberrant mDAN axons in nrp2 lacZ/lacZ mice were not indirectly mediated by alterations in S lit/ R obo signaling. Taken together, our results indicate that a novel mechanism mediated by N rp2 contributes to the establishment of uncrossed projections by m DAN axons.